High-risk Medulloblastoma
Conditions
Brief summary
The trial includes i) the evaluation of the efficacy of a treatment strategy, designed as a phase II trial, and ii) a dose-finding part. The Phase II trial is an open label, non-randomized, multicentre trial without control group. A Bayesian approach will be used to analyse the EFS, assuming a cure model. We will use three prior distributions of the EFS; (1) an enthusiastic prior distribution, (2) a pessimistic prior distribution, and (3) a non-informative prior distribution. As the patient outcomes in the trial will be recorded, the subsequent distribution of the outcome probability under experimental treatment will be computed by applying Bayes' theorem, which yields an estimated EFS probability with a 95% credibility interval (measure of Bayesian precision). Two interim analyses are planned to monitor the efficacy data (early stopping rules for futility or inefficacy). The final analysis of efficacy will be made on an intention to treat basis, including all recruited patients, 3 years after recruitment of the last patient. Due to the uncertainty on the dose of cyclophosphamide that can be given in combination with Busilvex for the last chemotherapy course in patients in complete response after intensification chemotherapy treatment, a dose-finding subtrial will be performed to address this issue (Phase I part). The dose escalation of cyclophosphamide will be performed using the Continual Reassessment Method in a Bayesian framework.
Interventions
Carboplatin 160 mg/m\^2 Day 1 to day 5, as an intravenous infusion over 1 hour. Dilution in 5 % glucose saline or sodium chloride 9 mg/ml (0.9%). Etoposide 100 mg/m\^2 D ay 1 to day 5, as an intravenous infusion over 1 hour. Dilution in physiological saline or 5 % glucose saline while not exceeding a concentration of 0.4 mg/ml etoposide in the infusion bottle.
DRUGThiotepa
Thiotepa 200 mg/m² Day-3 to day-1, as an intravenously infusion over 1 hour dilution in 200 ml/m\^2 of 5% glucose saline or sodium chloride 9 mg/ml (0.9%).
DRUGCyclophosphamide + Busilvex
Cyclophosphamide: * Level 1 20 mg/kg/day * Level 2 30 mg/kg/day * Level 3 40 mg/kg/day * Level 4 50 mg/kg/day Busilvex: \< 9 kgs 0.8 mg/kg/dose -\> 3.2 mg/kg/day; 9 à \< 16 kgs 0.96 mg/kg/dose -\> 3.84 mg/kg/day; 16 à 23 kgs 0.88 mg/kg/dose -\> 3.52 mg/kg/day; \> 23 à 34 kgs 0.76 mg/kg/dose -\> 3.04 mg/kg/day; \> 34 kgs -\> 0.64 mg/kg/dose.
DRUGTemozolimide + Irinotecan
During 2 cycles of 21 days: * Temozolomide: 100 mg/m\^2/day PO from Day 1 to Day 5; * Irinotecan: 10 mg/m\^2/day IV from Day 1 to Day 5 + from Day 8 to Day 12
COMBINATION_PRODUCTEtoposide + radiotherapy
* Etoposide: 35 mg/m\^2/day PO during 21days * Radiotherapy: 1.8 Gy/fraction/day (total dose: 54 Gy)
DRUGTemozolomide
150 mg/m\^2/day PO during 5 days, during 6 cycles of 21 days
Sponsors
Gustave Roussy, Cancer Campus, Grand Paris
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 5 Years
Healthy volunteers
No
Inclusion criteria
* Histological diagnosis of medulloblastoma with no INI-1 loss * High risk medulloblastoma defined by at least one of the following conditions: * Newly diagnosed classical metastatic medulloblastoma * Newly diagnosed anaplastic/large cell medulloblastoma or other unfavourable histology confirmed by review and coordinating investigator * Newly diagnosed medulloblastoma with amplification of c-myc or N-myc * Age at initial biopsy less or equal than 5 years * Weight compatible with leukapheresis * Ability to comply with requirements for submission of materials for central review * Nutritional and general status compatible with this therapy, Lansky play score \>/= 30% * Estimated life expectancy \>/=3 months * No organ toxicity other than neurological symptoms (grade \>2 according to NCI-Common Toxicity Criteria v4.0 grading system) * No prior irradiation or chemotherapy (except Vepesid - CBP) * Written informed consent from parents or legal guardian * All patients must be affiliated to a social security regimen or be a beneficiary of the same in order to be included in the study. Inclusion criteria for the Phase I part of the study: * Complete response after intensification phase confirmed by central review * Adequate hepatic and renal function
Exclusion criteria
* Desmoplastic medulloblastoma * Atypical Teratoid rhabdoid tumour * Uncontrolled active or symptomatic intracranial hypertension * Patient incapable of undergoing medical follow-up * Relapse of medulloblastoma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I - Maximum Tolerated Dose | From inclusion to the Dose Limiting Toxicity up to 12 months | To determine the Maximum Tolerated Dose (MTD) of cyclophosphamide in combination with a fixed dose of Busilvex in children with high-risk medulloblastoma who are in complete response after the intensification phase. |
| Phase II - Event Free Survival | From inclusion to Event up to 3 years | To assess the efficacy in terms of Event Free Survival (EFS) of the strategy intended to treat children younger than 5 years of age suffering from high-risk medulloblastoma with sequential high-dose chemotherapy without radiotherapy. |
Secondary
| Measure | Time frame |
|---|---|
| Radiotherapy-free survival without event | From inclusion up to 3 years |
| Overall Survival | From inclusion up to 3 years |
Countries
France
Outcome results
None listed